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|Jean H. Overmeyer, Ph.D.
Research Associate Professor of Biochemistry and Cancer Biology
Our lab has been studying the induction of a nonapoptotic cell death pathway in glioblastoma cells, termed methuosis. We originally reported the description of this cell death pathway following stimulation by activated HRas. Methuosis involves an induction of macropinocytosis, where the cells take up increased amounts of extracellular fluid, combined with defects in the endocytic trafficking pathway that lead to a vast accumulation of intracellular vacuoles. The metabolic activity of the cells become compromised, and attachment to the substratum is disrupted, leading to cell death. Since many cancers harbor mutations in genes required for apoptotic cell death, we were interested in identifying a drug-like molecule that could induce this non-apoptotic form of cell death. To this end, we characterized the induction of methuosis by a small molecule, MIPP. We've shown that MIPP stimulates macropinocytosis and the resulting vacuoles fuse and acquire characteristics of late endosomes, but accumulate prior to fusion with the lysosomes. MIPP treatment leads to a decline in the cellular ATP levels and a decrease in the mitochondrial membrane potential prior to nonapoptotic cell death. We've also shown that MIPP can induce methuosis in a variety of different cancer cells, as well as multiple glioblastoma cell lines. Of particular interest, MIPP can induce cell death in a glioblastoma cell line that displays resistance to temozolomide, a drug currently used to treat glioblastoma.
Glioblastoma cell undergoing methuosis
Additionally, we have been testing a library of MIPP-related compounds for their ability
to induce methuosis. We hope to find a compound that is even more potent than MIPP
and will overcome some of the solubility difficulties that we've observed with this
compound. We've also gathered some preliminary data using a MIPP-like drug in mouse
xenografts, demonstrating vacuole formation in cells near the drug injection site
into intracranial tumors. The goal of these studies is to identify a potent compound
capable of initiating targeted cell death for cancers that are refractory to apoptotic
1981-1984 B.S. (magna cum laude) Indiana University of Pennsylvania, Indiana, PA (Biology)
1985-1991 Ph.D. University of Kentucky, Lexington, KY (Biochemistry)
|2008-present||Research Associate Professor, Dept. of Biochemistry & Cancer Biology, University of Toledo, College of Medicine|
|1999-2007||Research Assistant Professor, Dept. of Biochemistry & Cancer Biology, University of Toledo College of Medicine (formerly Medical University of Ohio)|
|1998-1999||Assistant Professor of Cellular & Molecular Physiology, Penn State College of Medicine|
|1997-1998||Instructor, Cellular and Molecular Physiology, Penn State College of Medicine|
|1995-1997||Research Scientist, Geisinger Clinic, Weis Center for Research|
|1992-1995||Postdoctoral Fellow, Geisinger Clinic, Weis Center for Research|
Maltese, W.A., and Overmeyer, J.H. (2014) Methuosis: Nonapoptotic cell death associated with vacuolization of macropinosome and endosome compartments. Am. J. Pathol. 184:1630-1642.
Trabbic, C.J., Dietsch, H.M., Alexander, E.M., Nagy, P.I., Robinson, M.W., Overmeyer, J.H., Maltese, W.A., and Erhardt, P.W. (2014) Differential induction of cytoplasmic vacuolization and methuosis by novel 2-indolyl-substituted pyridinylpropenones. ACS Med. Chem. Lett. 5:73-77.
Robinson, M.W., Overmeyer, J.H., Young. A.M., Erhardt P.W. and Maltese, W.A. (2012) Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel type of non-apoptotic cell death. J. Med. Chem. 55:1940-1956.
Overmeyer, J.H., Young, A.M., Bhanot, H., and Maltese, W.A. (2011) A chalcone-related small molecule that induces methuosis, a novel form of non-apoptotic cell death, in glioblastoma cells. Molec. Cancer, 10:69.
Overmeyer, J.H. and Maltese, W.A. (2011) Death pathways triggered by activated Ras in cancer cells. Frontiers in Bioscience, 16:1693-1713.
Bhanot, H., Young, A.M., Overmeyer, J.H., and Maltese, W.A. (2010) Induction of nonapoptotic cell death by activated Ras requires inverse regulation of Rac1 and Arf6. Molec. Cancer Res., 8:1358-1374.
Overmeyer, J.H.*, Kaul, A.*, Johnson, E.E., and Maltese, W.A. (2007) Active ras triggers death in glioblastoma cells through hyperstimulation of macropinocytosis. Molec. Cancer Res., 6:965-977. (*equal contributors)
Kaul, A.*, Overmeyer, J.H.*, and Maltese, W.A. (2007) Activated Ras induces cytoplasmic vacuolation and non-apoptotic death in glioblastoma cells via novel effector pathways. Cell. Signalling19:1034-1043. (*equal contributors)
Johnson, E.E., Overmeyer, J.H., Gunning, W.T. and Maltese, W.A. (2006) Gene silencing reveals a specific function of hVps34 phosphatidylinositol 3-kinase in late versus early endosomes. J. Cell Sci.119:1219-1232.
Zeng, X., Overmeyer, J.H., and Maltese, W.A. (2006) Functional specificity of the mammalian Beclin-Vps34 PI 3-kinase complex in macroautophagy versus endocytosis and lysosomal enzyme trafficking. J. Cell Sci.119:259-270.
Overmeyer, J.H., and Maltese, W.A. (2005) Tyrosine phosphorylation of Rab proteins. Methods in Enzymology 403:194-202.
Ding, J.D., Soule, G., Overmeyer, J.H., and Maltese, W.A. (2003) Tyrosine phosphorylation of the Rab24 GTPase in cultured mammalian cells. Biochem. Biophys. Res. Commun.312:670-675.